Comprehensive analyses of DNA methylation of the TIMP3 promoter in placentas from early-onset and late-onset preeclampsia

Cruz, Juliana de Oliveira; Conceição, Izabela Mamede Costa Andrade da; Sandrim, Valéria C.; Luizon, Marcelo R.

doi:10.1016/j.placenta.2021.12.003

Cited by 7 publications

(6 citation statements)

References 21 publications

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“…20 Moreover, the lack of differences on plasma TIMP-3 levels between early-onset pre-eclampsia and late-onset pre-eclampsia reinforces our earlier results regarding DNA methylation and gene expression showing that TIMP-3 is not able to differentiate between these two pre-eclampsia phenotypes. 20 Although the pathogenesis of pre-eclampsia is not entirely known, placental malperfusion leading to widespread maternal endothelial dysfunction is accepted as a major disease mechanism. Hence, set as two pathophysiologic stages, abnormal placental formation occurs early in the first trimester followed by a maternal syndrome in the last two trimesters characterized by an excess of anti-angiogenic and pro-inflammatory factors.…”

Section: Discussionsupporting

confidence: 84%

“…Similarly, by means of a sub‐analysis of publicly available data deposited in the Gene Expression Omnibus, we have recently shown that DNA hypomethylation is specific for the promoter region of the TIMP3 gene, leading to increased TIMP3 mRNA levels 20 . Moreover, the lack of differences on plasma TIMP‐3 levels between early‐onset pre‐eclampsia and late‐onset pre‐eclampsia reinforces our earlier results regarding DNA methylation and gene expression showing that TIMP‐3 is not able to differentiate between these two pre‐eclampsia phenotypes 20 …”

Section: Discussionmentioning

confidence: 97%

“…The roles of TIMP‐3 in cardiovascular pathologies, namely myocardial disease, cardiac inflammation, aortic aneurysm, and atherosclerosis, are reviewed elsewhere, 7 as is its therapeutic potential and application as a biomarker for predicting cancer progression 19 . Our comprehensive analyses of DNA methylation of the TIMP3 promoter in placentas from early‐onset pre‐eclampsia and late‐onset pre‐eclampsia 20 confirmed that its promoter is hypomethylated and TIMP3 is overexpressed in placentas from women with pre‐eclampsia 21,22 . Increased TIMP3 mRNA levels resulting in increased TIMP‐3 protein production could inhibit the activity of MMPs, thereby leading to impaired trophoblast invasion and abnormal placentation in pre‐eclampsia.…”

Section: Introductionmentioning

confidence: 99%

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Circulating levels of tissue inhibitor of metalloproteinase 3, a protein with inhibitory effects on angiogenesis, are increased in pre‐eclampsia

Palei

Cruz

Chaguri

et al. 2022

Intl J Gynecology & Obste

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Objective To assess and compare circulating tissue inhibitor of metalloproteinase 3 (TIMP‐3) concentrations between women with pre‐eclampsia and healthy pregnant women. We also aimed to determine the relationships between circulating TIMP‐3 and matrix metalloproteinase 2 (MMP‐2), MMP‐9, TIMP‐1, and TIMP‐2 concentrations in pre‐eclampsia. Methods A primary case–control study included patients with pre‐eclampsia (n = 219) and gestational hypertension (n = 118), healthy pregnant women (n = 214), and non‐pregnant women (n = 66), and a replication case–control study included patients with pre‐eclampsia (n = 177) and healthy pregnant women (n = 124), all from southeastern Brazil. Plasma TIMP‐3, MMP‐2, MMP‐9, TIMP‐1, and TIMP‐2 concentrations were assessed using commercially available enzyme‐linked immunosorbent assay kits, and the relationships between them were analyzed using Spearman's correlation. Results In our primary study, patients with pre‐eclampsia and gestational hypertension exhibited increased TIMP‐3 concentrations compared with healthy pregnant women (both P < 0.0001) and non‐pregnant women (both P < 0.001). These findings were confirmed in the replication study, showing elevated TIMP‐3 concentrations in women with pre‐eclampsia versus healthy pregnant women (P < 0.001). We found no difference in TIMP‐3 concentrations between early‐onset and late‐onset pre‐eclampsia. Moreover, TIMP‐3 concentrations were significantly correlated with plasma concentrations of TIMP‐1 (r = 0.2333; P = 0.0086) and MMP‐2 (r = 0.2159; P = 0.0156) in pre‐eclampsia. Conclusions Circulating TIMP‐3 concentration is increased in women with pre‐eclampsia compared with healthy pregnant women, and it is positively correlated with plasma MMP‐2 and TIMP‐1 concentrations in pre‐eclampsia.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Circulating levels of tissue inhibitor of metalloproteinase 3, a protein with inhibitory effects on angiogenesis, are increased in pre‐eclampsia

Palei

Cruz

Chaguri

et al. 2022

Intl J Gynecology & Obste

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“…Regarding the role of TIMP-3 in PE, the promoter polymorphism rs9619311 was not associated with response to antihypertensive therapy (Luizon et al, 2014). However, we identified a higher number of significant differentially methylated probes located on the TIMP-3 promoter, as well as an increased TIMP-3 expression in corresponding placental samples from early-onset PE compared to controls, which denotes DNA methylation of TIMP-3 promoter as an epigenetic mechanism in PE (Cruz et al, 2022). Recently, we found that circulating TIMP-3 is increased in patients with PE compared with healthy pregnancy, and these TIMP-3 levels were positively correlated with MMP-2 and TIMP-1 concentrations in PE (Palei et al, 2022).…”

Section: Matrix Metalloproteinase (Mmp)-2 and Tissue Inhibitor Of Met...mentioning

confidence: 66%

Antihypertensive therapy responsiveness and adverse outcomes in preeclampsia: insights into molecular mechanisms underlying cardiovascular and renal complications

Luizon,

Pereira,

Mamede

et al. 2023

Front. Pharmacol.

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IntroductionPreeclampsia (PE) is a multisystem disorder that affects 2%-8% of pregnancies worldwide and is a leading cause of maternal and fetal morbidity and mortality (Duley, 2009). PE is defined as new-onset maternal blood pressure greater than 140/90 mmHg after the 20th week of pregnancy that occurs along with proteinuria or other indications of renal insufficiency, thrombocytopenia, liver dysfunction, pulmonary edema, and cerebral disturbances (American College of Obstetricians and Gynecologists, 2013). The pathogenesis of PE is multifactorial with recognized placental, vascular, renal, and immunological contributions (Turbeville and Sasser, 2020).PE is characterized by defective placentation, abnormal spiral artery remodeling, placental ischemia, oxidative stress at the maternal-fetal interface, and angiogenic imbalance in the maternal circulation, thereby resulting in endothelial dysfunction and end-organ damage (Phipps et al., 2019). Noteworthy, several studies ratify the relationship of PE with future risk for cardiovascular disease, and accumulating evidence suggests an association of PE with long-term renal disease, although further studies on the mechanisms underlying this increased risk are needed (Turbeville and Sasser, 2020). However, significant knowledge gaps still exist in identifying the mechanisms that link placental ischemia to maternal systemic vascular and renal dysfunction (Wang et al., 2023).Current treatment strategies for PE focus on stabilizing the maternal symptoms in order to prolong pregnancy and allow additional fetal development, and managing maternal

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“…Moreover, it exerts anti-angiogenic effects by inhibiting cell proliferation and migration through inhibition of MMPs and interference with the binding of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) [ 34 , 35 ]. Cruz et al detected a hypomethylated TIMP3 promoter in the placental samples from patients with preeclampsia [ 36 ].…”

Section: Timp3 Biologymentioning

confidence: 99%

Tissue Inhibitor of Metalloproteinase 3: Unravelling Its Biological Function and Significance in Oncology

Lee,

Wu,

Cheng

et al. 2024

IJMS

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Tissue inhibitor of metalloproteinases-3 (TIMP3) is vital in regulating several biological processes. TIMP3 exerts antitumour effects via matrix metalloproteinase (MMP)-dependent and MMP-independent pathways. Due to promoter methylation and miRNA binding, TIMP3 expression has been observed to decrease in various cancers. Consequently, the migration and invasion of cancer cells increases. Conflicting results have reported that expression levels of TIMP3 in primary and advanced cancers are higher than those in healthy tissues. Therefore, the role of TIMP3 in cancer biology and progression needs to be elucidated. This review provides an overview of TIMP3, from its biological function to its effects on various cancers. Moreover, gynaecological cancers are discussed in detail. TIMP3 has been associated with cervical adenocarcinoma as well as cancer development in serous ovarian cancer and breast cancer metastasis. However, the relationship between TIMP3 and endometrial cancers remains unclear. TIMP3 may be a useful biomarker for gynaecological cancers and is a potential target for future cancer therapy.

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Comprehensive analyses of DNA methylation of the TIMP3 promoter in placentas from early-onset and late-onset preeclampsia

Cited by 7 publications

References 21 publications

Circulating levels of tissue inhibitor of metalloproteinase 3, a protein with inhibitory effects on angiogenesis, are increased in pre‐eclampsia

Circulating levels of tissue inhibitor of metalloproteinase 3, a protein with inhibitory effects on angiogenesis, are increased in pre‐eclampsia

Antihypertensive therapy responsiveness and adverse outcomes in preeclampsia: insights into molecular mechanisms underlying cardiovascular and renal complications

Tissue Inhibitor of Metalloproteinase 3: Unravelling Its Biological Function and Significance in Oncology

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